tbuckley/cabot-search huggingface dataset:
Omission of Upfront Craniospinal Irradiation in Patients with Low-Risk WNT-Pathway Medulloblastoma Is Associated with Unacceptably High Risk of Neuraxial Failure
Authors: Tejpal Gupta, Shizan Pervez, Archya Dasgupta, Abhishek Chatterjee, Sridhar Epari, Girish Chinnaswamy, Rakesh Jalali
Journal: Clinical Cancer Research (2022)

Medulloblastoma is a heterogenous disease comprising four molecular subgroups: wingless (WNT), sonic hedgehog (SHH), group 3, and group 4, respectively. Excellent long-term outcomes have prompted deintensification of therapy in WNT-pathway medulloblastoma. We assessed the safety of avoiding upfront craniospinal irradiation (CSI) in children with low-risk WNT-pathway medulloblastoma.Children with low-risk WNT-pathway medulloblastoma were treated with postoperative focal conformal radiotherapy, avoiding upfront CSI, followed by six cycles of adjuvant systemic chemotherapy. A group-sequential design (triangular test) with predefined stopping rules if the rate of relapse exceeded 15% at 2 years was incorporated to ensure the safety of study participants.7 children with low-risk WNT-pathway medulloblastoma were accrued after written informed consent/assent and treated as per protocol. One child died of neutropenic sepsis and multiorgan dysfunction during chemotherapy. Three children were detected with neuraxial failure (supratentorial brain and/or spine) on surveillance neuro-imaging within 2 years from index diagnosis, leading to premature study termination. At relapse, children were treated with salvage CSI plus boost irradiation of metastatic deposits followed by second-line chemotherapy. Two of them continue to be in remission (32 and 26 months after first relapse), while one child developed a second relapse, necessitating further systemic chemotherapy and craniospinal reirradiation, resulting in excellent clinico-radiologic response. At a median follow-up of 42 months, the 2-year Kaplan-Meier estimates of event-free survival, recurrence-free survival, and overall survival were 42.9%, 50%, and 85.7% respectively.Omission of upfront CSI in low-risk WNT-pathway medulloblastoma is associated with an unacceptably high risk of neuraxial failure. See related commentary by Remke and Ramaswamy, p. 4161.
Abstract 3945: Novel antagonists of TEAD palmitoylation inhibit the growth of Hippo-altered cancers in preclinical models
Authors: Adeela Kamal, Aurélie Candi, Matthias Versele, Bart Vanderhoydonck, Arnaud Marchand, Ron de Jong, Thuy Hoang, Georg Halder, Patrick Chaltin, Stephen L. Gwaltney, Mike Burgess
Journal: Cancer Research (2022)

Abstract Background: The Hippo pathway is an evolutionarily conserved signaling cascade whose deregulation can promote excessive cell proliferation and tumor development. Pathway output is mediated by the YAP and TAZ transcriptional co-activators, which bind to TEAD family transcription factors to drive target gene expression. Genomic aberrations in Hippo pathway components result in constitutive activation of YAP/TAZ, as seen with NF2 mutations in subsets of mesothelioma and other cancers. Hyperactivation of YAP/TAZ has also been associated with resistance to a variety of targeted agents, including EGFR and CDK4/6 inhibitors, suggesting that targeting the pathway may have utility as part of rationally selected combinations, in addition to genomically-informed monotherapy applications. Activity of the YAP/TAZ-TEAD complex thus represents a compelling pharmacologic target, due to its essential role in the pathway, and the presence of a conserved druggable site in TEAD that is required for transcriptional function. Results and Discussion: Using biophysical techniques, we identified novel small molecules that bind to the TEAD auto-palmitoylation pocket. Initial hits were optimized for antagonism of TEAD-based transcription and drug-like properties, ultimately producing highly potent and orally bioavailable TEAD inhibitors. These compounds selectively inhibited the proliferation of cancer cell lines harboring genomic alterations in the Hippo pathway with low nM potency. In vivo models of Hippo pathway-altered xenografts showed consistent monotherapy activity, with dose-dependent and durable tumor regressions achieved at well-tolerated doses. Further characterization of these compounds as monotherapies and as part of rationally-designed combination regimens is ongoing. Citation Format: Adeela Kamal, Aurélie Candi, Matthias Versele, Bart Vanderhoydonck, Arnaud Marchand, Ron de Jong, Thuy Hoang, Georg Halder, Patrick Chaltin, Stephen L. Gwaltney, Mike Burgess. Novel antagonists of TEAD palmitoylation inhibit the growth of Hippo-altered cancers in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3945.
Circulating tumor DNA: current challenges for clinical utility
Authors: Donna K. Dang, Ben H. Park
Journal: Journal of Clinical Investigation (2022)

Cancer cells shed naked DNA molecules into the circulation. This circulating tumor DNA (ctDNA) has become the predominant analyte for liquid biopsies to understand the mutational landscape of cancer. Coupled with next-generation sequencing, ctDNA can serve as an alternative substrate to tumor tissues for mutation detection and companion diagnostic purposes. In fact, recent advances in precision medicine have rapidly enabled the use of ctDNA to guide treatment decisions for predicting response and resistance to targeted therapies and immunotherapies. An advantage of using ctDNA over conventional tissue biopsies is the relatively noninvasive approach of obtaining peripheral blood, allowing for simple repeated and serial assessments. Most current clinical practice using ctDNA has endeavored to identify druggable and resistance mutations for guiding systemic therapy decisions, albeit mostly in metastatic disease. However, newer research is evaluating potential for ctDNA as a marker of minimal residual disease in the curative setting and as a useful screening tool to detect cancer in the general population. Here we review the history of ctDNA and liquid biopsies, technologies to detect ctDNA, and some of the current challenges and limitations in using ctDNA as a marker of minimal residual disease and as a general blood-based cancer screening tool. We also discuss the need to develop rigorous clinical studies to prove the clinical utility of ctDNA for future applications in oncology.
Abstract 5013: Integrated analysis of intragastric microbiome and human gene expression uncovers genetic, microbial, and immunological associations in gastritis and gastric cancer
Authors: Chan Hyuk Park, Changjin Hong, A-reum Lee, Jaeyun Sung, Tae Hyun Hwang
Journal: Cancer Research (2022)

Abstract Background: Gastric carcinogenesis has been found to be associated with intragastric microbiome, gastric mucosal gene expression, and immune cells comprising the tumor microenvironment separately in independent studies. However, to date, there has been no multi-omic investigations analyzing these biological traits simultaneously. Thus, there is a paucity in our understanding of the intricate relationship between intragastric microbes and the host in gastric disease. To address this gap, we aimed to comprehensively investigate the microbiome, host gene expression, and immune cells in the stomach across a range of different states along the gastric carcinogenesis pathway. Methods: Gastric biopsy samples were obtained from healthy individuals or patients with gastritis or gastric cancer (biopsy cohort, n=30). Surgical samples (of cancer and adjacent severe gastritis tissues) were obtained from gastric cancer patients (surgery cohort, n=40). Using 16S rRNA gene sequencing, RNA-seq, and cell-type enrichment analysis of each participant’s biospecimens, we identified associations between the microbiome and host transcriptome or inferred immune cell types. Results: Microbiome composition and gene expression patterns showed significant differences between disease states (healthy, gastritis, or cancer). Expression of ‘Cell cycle’ pathway genes was enriched in gastric cancer in both biopsy and surgery cohorts. In the biopsy cohort, Helicobacteraceae, which was abundant in gastritis, was highly correlated with FAM3D, which was previously found to be involved in gastrointestinal inflammation. In the surgery cohort, Lachnospiraceae, which was abundant in gastric cancer, was highly correlated with UBD, which is known to regulate mitosis and reduce cell cycle time. Cell-type enrichment analysis revealed lower B cell infiltration in gastric cancer than in gastritis (both cohorts). Tissue-infiltrating B cells were associated with Helicobacteraceae. Conclusions: Associations between the intragastric microbiome, human gene expression, and tissue-infiltrating immune cells are unique to gastric disease state. The findings herein may aid the discovery of novel biomarkers or therapeutic targets of gastric cancer. Citation Format: Chan Hyuk Park, Changjin Hong, A-reum Lee, Jaeyun Sung, Tae Hyun Hwang. Integrated analysis of intragastric microbiome and human gene expression uncovers genetic, microbial, and immunological associations in gastritis and gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5013.
Impact of BCR::ABL1 transcript type on RT-qPCR amplification performance and molecular response to therapy
Authors: Matthew Salmon, Helen E. White, Hana Zizkova, Andrea Gottschalk, Eliska Motlova, Nuno Cerveira, Dolors Colomer, Daniel Coriu, Georg N. Franke, Enrico Gottardi, Barbara Izzo, Tomas Jurcek, Thomas Lion, Vivien Schäfer, Claudia Venturi, Paolo Vigneri, Magdalena Zawada, Jan Zuna, Lenka Hovorkova, Jitka Koblihova, Hana Klamova, Marketa Stastna Markova, Dana Srbova, Adela Benesova, Vaclava Polivkova, Daniela Zackova, Jiri Mayer, Ingo Roeder, Ingmar Glauche, Thomas Ernst, Andreas Hochhaus, Katerina Machova Polakova, Nicholas C. P. Cross
Journal: Leukemia (2022)

Abstract Several studies have reported that chronic myeloid leukaemia (CML) patients expressing e14a2 BCR::ABL1 have a faster molecular response to therapy compared to patients expressing e13a2. To explore the reason for this difference we undertook a detailed technical comparison of the commonly used Europe Against Cancer (EAC) BCR::ABL1 reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) assay in European Treatment and Outcome Study (EUTOS) reference laboratories ( n = 10). We found the amplification ratio of the e13a2 amplicon was 38% greater than e14a2 ( p = 0.015), and the amplification efficiency was 2% greater ( P = 0.17). This subtle difference led to measurable transcript-type dependent variation in estimates of residual disease which could be corrected by (i) taking the qPCR amplification efficiency into account, (ii) using alternative RT-qPCR approaches or (iii) droplet digital PCR (ddPCR), a technique which is relatively insensitive to differences in amplification kinetics. In CML patients, higher levels of BCR :: ABL1/GUSB were identified at diagnosis for patients expressing e13a2 ( n = 67) compared to e14a2 ( n = 78) when analysed by RT-qPCR ( P = 0.0005) but not ddPCR ( P = 0.5). These data indicate that widely used RT-qPCR assays result in subtly different estimates of disease depending on BCR::ABL1 transcript type; these differences are small but may need to be considered for optimal patient management.
PD-L1 Crosslinking as a New Strategy of 4-1BB Agonism Immunotherapy
Authors: Fei Shu, Salman R. Punekar, Vamsidhar Velcheti, Miguel F. Sanmamed, Jun Wang
Journal: Clinical Cancer Research (2022)

Summary 4-1BB has been considered a promising target in cancer immunotherapy for decades. Nevertheless, early 4-1BB–targeted agents demonstrated significant liver immuno-toxicity. A new wave of 4-1BB–based therapy is being developed to circumvent hepatotoxicity with a bispecific molecule that directs 4-1BB agonism to the tumor microenvironment by targeting tumor-associated immune checkpoint molecule PD-L1. See related article by Peper-Gabriel et al., p. 3387
Abstract 369: Improving the nanomaterial delivery by using cell-penetrating peptides in the bystander manner
Authors: Yue-Xuan Li, Yushuang Wei, Hong-Bo Pang
Journal: Cancer Research (2022)

Abstract While nanoparticles (NPs) can be useful to improve the diagnosis and treatment of various diseases including cancer, a major limiting factor for their applications is the poor efficiency of cell entry. A common solution to this problem is to covalently link NPs with cell-penetrating peptides (CPPs), such as the transactivator of transcription (TAT) peptide. A few cationic CPPs were previously shown to increase the cellular uptake of co-administered, but not covalently coupled, NP cargo through an endocytic pathway, macropinocytosis. This so-called bystander uptake process is of unique advantage for NP intracellular delivery as it bypasses the requirements of additional chemical modifications. Here, we set out to determine whether other classes of CPPs (e.g. hydrophobic and amphiphilic) exhibit similar bystander activities, and what physico-chemical properties of NPs affect the bystander uptake process. First, we discovered that transportan (TP) peptide, an amphiphilic CPP, can initiate similar bystander uptake process for a variety of NPs and solute tracers. TP-induced bystander uptake relies on macropinocytosis as well, and occurs in a variety of cell types and in physiological tissues. Second, using TAT-functionalized NPs to stimulate the bystander effect, we showed that the bystander activity depends on the size of bystander NPs, with an optimal range around 50 nm in diameter. Compared to rod-like and triangular NPs, spherical NPs showed higher uptake in the bystander manner. Additionally, we investigated how CPP-NPs, once inside cells, get out of one cell and enter another, and found again that NP sizes affect the efficiency of CPP-NP intercellular transport as well. Overall, these efforts lay the foundation to further understand the bystander activity of CPP-assisted cell entry and improve the efficacy of nanomedicine in cancer and other human diseases. Citation Format: Yue-Xuan Li, Yushuang Wei, Hong-Bo Pang. Improving the nanomaterial delivery by using cell-penetrating peptides in the bystander manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 369.
Abstract 3808: Spatially resolved transcriptomics of cellular architecture in EGFR-mutated lung cancer
Authors: Daniel L. Kerr, Wei Wu, Whitney Tamaki, Anatoly Urisman, Yu-Ting Chou, Philippe Gui, David M. Jablons, Trever G. Bivona, Collin M. Blakely
Journal: Cancer Research (2022)

Abstract Introduction: Single-cell RNA sequencing of dissociated tumors enables the profiling of cellular states in fine detail, but erases the cellular organization of the analyzed tissue. Spatially resolved transcriptomics (SRT) using 10X Genomics’ Visium platform combines histological staining and RNA sequencing by capturing each transcript across spatially barcoded microarrays. SRT yields gene-expression matrices resolved within 55-micron array spots, and creates opportunities to explore how lung biology is affected by lung adenocarcinoma and how tumor cells and the proximal microenvironment are modulated by targeted therapy. Methods: SRT reactions (n=8) were performed on surgical specimens from human lung adenocarcinomas driven by kinase domain mutations of EGFR (exon 19 deletion, L858R point mutation, exon 20 insertion). SRT reactions analyzed primary lung cancer (n=5) or paired tumor-adjacent lung tissues (n=3). Results: 28458 array spots were recorded across all samples, and array spots captured a median of 5800 total transcripts and a median of 2416 unique transcripts. Single marker gene expression and unsupervised clustering across array spots corresponded with histological annotations of lung structures and adenocarcinoma. Integration of single-cell RNA sequencing data from lung adenocarcinoma specimens permitted mapping and quantification of 15 major cell types, including cancer cells, T- and B- lymphocytes, macrophages, dendritic cells, fibroblasts, and endothelial cells. Compared with paired tumor-adjacent lung tissues, adenocarcinoma tissues contained fibroblast-enriched desmoplasia and B-cell enriched tertiary lymphoid structures. In a clinical case with resistance to Osimertinib, the standard tyrosine kinase inhibitor, gene signature analysis of cancer-containing array spots revealed enrichment of gap-junction, fatty acid metabolism, and kynurenine pathway signatures compared to treatment naïve array spots. Conclusion: This pilot study demonstrates the feasibility of using SRT in lung adenocarcinoma. Paired with a single-cell atlas of lung adenocarcinoma during targeted therapy, this approach enables hypothesis-generation to investigate the alterations of tumor and tumor microenvironmental architecture in relation to targeted therapy. Citation Format: Daniel L. Kerr, Wei Wu, Whitney Tamaki, Anatoly Urisman, Yu-Ting Chou, Philippe Gui, David M. Jablons, Trever G. Bivona, Collin M. Blakely. Spatially resolved transcriptomics of cellular architecture in EGFR-mutated lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3808.
Abstract 3163: PR/STAT3 nuclear transcriptional complexes mediate aurora-A kinase-induced stemness plasticity in ER+ breast cancer
Authors: Antonino B. D'Assoro
Journal: Cancer Research (2022)

Abstract Purpose: Emergence of de novo or acquired resistance to standard of care endocrine therapies represents a major challenge in the clinical management of estrogen receptor alpha positive (ER+) breast tumors. This process is characterized by high tumor plasticity that confers to cancer cells the ability to shift from a differentiated state, with limited tumorigenic potential, to an undifferentiated state which is responsible for drug resistance and tumor relapse. In ER+ breast tumors, this plasticity is manifest by the enrichment of breast tumor initiating cells (BTICs) with stemness features, such as self-renewal capacity, CD44 expression and high ALDH activity, and ER down-regulation. Development of clinically relevant ER+ breast tumor models to test novel therapeutic strategies that inhibit the enhanced tumor cell plasticity and restore or extend endocrine sensitivity are urgently needed. Experimental Design: Unique endocrine resistant and metastatic breast cancer models were utilized to define in vitro and in vivo the pivotal role of Aurora-A mitotic kinase (AURKA) in the induction of stemness plasticity, endocrine therapy resistance and tumor progression. Unbiased phospho-proteomic analysis was performed in the absence or presence of alisertib, a clinically relevant AURKA inhibitor, that was used to identify novel down-stream targets of AURKA signaling pathway. Results: Phospho-proteomic analysis showed that AURKA targeting reduced the phosphorylation of STAT3 transcription factor at the serine-727 site. Significantly, herein we define a novel mechanism by which AURKA-induced self-renewal capacity is mediated through the activation of a phosphorylated serine727-STAT3/serine294-progesterone receptor (PR) transcriptional complex that regulates the expression of KLF4 stemness reprogramming gene. Remarkable, pharmacologic and genetic targeting of AURKA/STAT3/PR oncogenic axis impairs self-renewal capacity of endocrine therapy resistant breast cancer cells. Conclusions: In this study we demonstrate the pivotal role of a novel AURKA/STAT3/PR oncogenic axis in promoting stemness plasticity and endocrine therapy resistance. These findings provide the strong preclinical rationale for the development of novel combinatorial therapeutic strategies targeting cooperative AURKA/serine727-STAT3 and serine294-PR pathways predicted to result in the selective eradication of CD44High/ALDHHigh BTICs from the bulk tumor with consequent benefits to the clinical outcomes of patients with advanced ER+ breast cancer refractory to standard of care endocrine therapy. Citation Format: Antonino B. D'Assoro. PR/STAT3 nuclear transcriptional complexes mediate aurora-A kinase-induced stemness plasticity in ER+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3163.
Abstract 2323: A bioenergetic functional screening assay workflow to identify, validate, and characterize anti-cancer compounds
Authors: Yoonseok Kam, Lisa Winer, Natalia Romero
Journal: Cancer Research (2022)

Abstract As bioenergetic metabolism is recognized as a critical activity supporting cell proliferation, differentiation, and even death, many proposed targets for cancer therapy are functionally linked to cellular bioenergetic metabolism. Here, we introduce an assay workflow for screening and analyzing potential anticancer drugs affecting cellular metabolism using extracellular flux analysis. The Agilent Seahorse XF Real-Time ATP rate assay can be used as a starting point to identify therapeutic compounds that induce a perturbation in metabolic phenotype. It provides a quantitative comparison of basal mitochondrial and glycolytic activities using the universal unit of ATP production rate. Through this initial comparative screening, the effect of different compounds on basal energetic state and pathway-specific metabolic perturbations can be identified providing information that cannot be assessed by intracellular ATP level measurements or cytotoxicity assays. A more comprehensive functional analysis can then be applied to validate the target mode of action through pathway-specific analysis tools such as the XF Cell Mito Stress Test and the XF Glycolytic Rate Assay. In this study, we tested the proposed workflow in three different NSCLC cell lines with different genetic backgrounds using a mock panel of known metabolic modulators including thiosemicarbazones, EGFR inhibitors, KRAS inhibitors, a glutaminase inhibitor, a Glut1 inhibitor, a chemotherapy drug, and a radiotherapy sensitizer candidate. The ATP production rate data from lung cancer cell lines exposed for 1 hour or 24 hours to the compounds, successfully identified the effects of metabolic pathway-specific modulation as well as metabolic phenotypic switching. In addition, dose-response studies using cell lines with different genetic backgrounds demonstrated differential susceptibility to the tested compounds. The workflow was then applied using a broader panel of 72 potential mitochondrial toxicants compounds. The assay could identify potent mitochondrial and glycolytic suppressor compounds effective on A549, a lung cancer cell line. A more comprehensive XF analysis then validated the mode of action for the identified metabolic suppressors. These results demonstrate the benefit of using the XF Real-Time ATP rate assay as an initial assay to uncover novel metabolic targets in early drug discovery research, guiding further research toward functional validation with the appropriate comprehensive XF assays. Citation Format: Yoonseok Kam, Lisa Winer, Natalia Romero. A bioenergetic functional screening assay workflow to identify, validate, and characterize anti-cancer compounds [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2323.